Radiation therapy induces cellular senescence in lymphatic endothelial cells, triggering increased expression of senescence markers p53, p21, and p16, along with elevated senescence-associated β-galactosidase activity. In a murine tail lymphedema model, radiation-treated mice maintained swelling for 30 days compared to controls that recovered, with corresponding increases in senescent cells and apoptosis. Cancer lymphedema patients who received radiation showed elevated plasma levels of senescence-related cytokines compared to surgery-only patients. This research fundamentally reframes our understanding of radiation-induced lymphatic damage. While radiation's immediate cytotoxic effects on lymphatic vessels are well-established, this study reveals that persistent cellular senescence creates a self-perpetuating cycle of tissue dysfunction. The senescent cells continue producing inflammatory signals long after treatment ends, explaining why radiation-related lymphedema often worsens over time rather than healing. The successful use of venetoclax, a BCL-2 inhibitor that selectively eliminated senescent cells and reduced swelling, opens promising therapeutic avenues. This represents a paradigm shift from viewing lymphedema as irreversible structural damage to a potentially treatable senescence-driven condition.